CA2493305A1 - Device for modulation of neuronal activity in the brain by means of sensory stimulation and detection of brain activity - Google Patents

Abstract

The invention relates to a device for controlled modulation of physiological and pathological neuronal rhythmic activity in the brain by means of sensory stimulation, which is capable of diagnostically ascertaining functional disorders in the brain and of alleviating or eliminating the symptoms of a functional disruption. According to the invention, the device comprises a control unit (4), a stimulator (1) and at least one means for detecting brain activity, said means being connected to the control unit (1).

Description

~, CA 02493305 2005-O1-27 23158 Traasl. of PCT/DE2003/002250 T R A N S L .fir T I O N
D a s c r i ~a t i o a DEVICE FOR MODULATION OF NEURONAL Av:TIYITY IN THE BRAIN BY MEANS OF
SENSORY STIMULATION AND DES"ECTION OF BRAIN ACTIVITY
The invention relates to a device for the need-controlled modulation of physiological and pathological neuronal rhythmic activity is the brain by means of sensory stimulation.
To diagnose the excitation processes of the brain, typically stimulation techniques like continuous excitation, multiple single excitations and periodic excitations or stimulations have bees used. For continuous stimulation, for example, continuous sound or visual patterns are considered.
Individual excitations result for example is so-called acoustic or visually evoked potentials. As periodic excitation, a stimulation with flickering light can be used, f or example, to diagnose a photosensitive epilepsy. Based for example on excitation responses of the brain or the sense organs as measured by means'of electrodes and the psychophysical findings (for example the number of recognized patterns or heard sounds) conclusions can be drawn as to the functioning of the sensory syste~ explored.

23158 Traasl. of PCT/DE2003/002250 =n biofeedback training, ~~ptical or acoustic feedback effects are therapeutically used to bring about in the patient a voluntary control of some action of the patieat~s bodily function, especially the sympathetic nervous ~aystem, is a desired manner.
The feedback signals enable, therefore, a self-control and increase the influence upon the bodily fuact:.oa which pertains by the patient. Applications of biofeedback training for examwple include applications is functional heart co:editions and neuromuscular stress states. With previous diagac~stic methods, the dependency between excitation responses and thE~ particular activity were not explored is detail. Only a relativE~ly few parameters of cerebral activity were investigated. With tt~e standard process it is not possible to match the stimulation tc~ the specific rhythmic brain activity of individual patients so a.s to be able to detect significantly snore functional and response ranges. It is especially not possible to investigate the effect of targeted manipulations is rhythmic cerebral x rain activity is different frequency regions (for example their amplitude damping) sad different brain areas oa information processing.
It is a prerequisite of biofeedback training that the patient voluntarily sad willingly desires the improved bodily function and participates therein. With most of the organ systems of the body sad for many brain functions this is not the case however or is not the case to a sufficient degree. Difficulties are encountered when the patient has a cerebral disorder, for exa~le, is a neglected patient following a brain infarct or has some other illness or medical condition following as illness which -a-23158 Traasl. of PCT/DE2003/002250 interferes with understanding or rec:ognitioa and which disables a voluntary effect even on simple bodily functions, makes them more difficult or even impossible. Thus neglect patients whose body parts ao longer respond can be scar<:ely responsive to biofeedback training at least with respect to the body parts which are nonrespoasive.
It is thus an object of the invention to provide a device which enables the need-directed modulation of the physiological or .pathological neuronal rhythmic acti~~ity of the brain. The device should be~able to reliably and suit~.bly diagnose functional disturbances of the brain and to ameliorate or eliminate the symptoms. Ia addition the device st.ould enable brain activity, which is relevant for sensory iafora~atioa processes to be investigated and manipulated for diagnostic and therapeutic purposes. Ia addition the device should so operate that with many patients is which the illness may have resulted is at least one bodily function to be ao longer capable of voluntary influence, the control of that bodily function to xe improved or restored.
Starting from the preamble of claim 1, these objects are attained with the features given in the characterizing clause of claim 1.
with the features of the invention it is possible directly to modulate in an as-required manner the physiological or pathological neuronal rhythmic activity of the brain so that it comes close to its natural function or is identical therewith. The device is suitable for reliably diagnosing functional disturbances of the brain and symptomatically ameliorating them or eliminating 23158 Traasl. of PCT/DE2003/002250 them. The device enables a new dia~~aostic method to be carried out is which, matched to the existing o:~ present rhythmic brain activity of a patient, a targeted m~:aipulatioa of the rhythmic activity is possible is different b~-aia regions. In this manner the neuronal information processing can be diagnostically and therapeutically explored sad modulai:ed. Furthermore, the device of the invention operates is such manna:r that the problem that many patients have many bodily functions which cannot be voluntarily influenced, can be overcome. Advaat:ageous further features of the invention are gives is the dependent: claims.
The drawing shows an exenu~lary configuration of the device according to the invention i=mblock diagram form for patients as well as several pulse sequences involved in the diagnosis and treatment.
Ia the drawing:
FIG. 1: A block diagram c~f the device.
FIG. 2: A stimulus sequence for excitation at the resonant frequency at which, for the purpose of desynchronizatioa, a single pulse is applied is the vulnerable phase.
FIG. 3a: Aa example of the course of the patters over time of the sensorial excitation prcduced by mesas for generating the sensorial excitations 1.
FIG. 3b: A schematic illustration of the activity pattern of the brain region having the disorder sad associated with the illustration is FIG. 3a.

23158 Transl. of PCT/DE2003/002250 FIG. 4a: A scan of the excitation frequency with which the frequency of the pulse sequence slowly varies.
FIG. 4b: A rise of the at~tural rhythmic activity.
FIG. 5a-f: Schematic ill»stratioas of the resetting curves of a phase associated with a standardization process:
FIG. 6: A flow diagram i:or the mode of operation according to the invention of the dESVice.
FIG. 1 shows a device with a stimulator 1 (la, 1b) in frost of which a patient is seated. Oa the head of the patient a sensor 2 is applied, the sensor 2 being connected by as isolating amplifier 3 to a control unit 4. Tt.e device comprises a receiver 5, which also is connecte8 to the control unit 4 sad which can register the reactions of the patie~.t. Ia addition, the device encompasses a means for monitoring the stimulation 6 which is applied over a means for data processing sad for displaying the data so that the results can be visually and/or auditorially delivered to the investigator. The control unit 4 is connected with the mesas 6 for monitoring the stimulation. The sensor 2, the receiver 5, the stimulator 1 sad the mesas 6 for monitoring the stimulation can also be is a contact-free connection with the control unit 4, for example through transmitters sad receivers.
FIG. 2 shows a schematic pattern of a pulse sequence for a repetitive application. This pulse sequence has a periodic succession of pulses sad is followed by a desynchroaizatioa pulse (last pulse). The frequency of the periodic pulse sequence is the resonance frequency of the rhythm to be desynchronized. The 23156 Traasl. of PCT/DE2003/002250 purpose of the pulse sequence is to effect as eatrainmeat which controls the phase dynamic of the rhythm to be desynchronized.
After a constant time interval, the desyachronization pulse is applied in the vulnerable phase of ~:he neutral rhythm. The abscissa is a time axis is nay opts«nally selected unit while the ordinate gives as intensity of the excitation also is any selected unit.
FIG. 3a again has as absc~.ssa formed by a time axis is any chosen units and an ordinate wh~.ch gives as intensity of the excitation also in selective units. The time segments T1 and Ts as well as T~ and T5 correspond to the ~;onfiguration is FIG. 2. Ia the time segment T3, a periodic excitati~a sequence is supplied whose frequency differs from the resonaacE~ frequency of the neural population to be desynchronized. Ii, the time segments T1 and Ts as well as T~ and Ts, the desyachroaizimg stimulation illustrated is FIG. 2 are respectively carried out.
In FIG. 3b, the abscissa f.as a time axis which has the same time units as is FIG. 3a. The ordinate indicates schematically the amplitude as a fu~ctioa of time in a sliding time window of the rhythm to be desynchrcaized is optional waits. The time segments T~k are identical with the time segments Tk, whereby k l, 2, 3, 4, 5. During the eatraiameat is time segment T1, apart from a control of the phase dynamic there is additionally a resonance-like amplification of the amplitude. The desynchronizing individual excitation in the time segment T~s encounters the neuronal rhythm is its vulnerable phase and desynchronizes it so that at the end of this stimulation the amplitude is miasmal. Ia 23158 Traasl. of PCT/DE2003/002250 time segment T, there is further sensor stimulus so that the patient can accomplish his goals, fc~r exaa~le, the detection of special patterns in as oa-going manner. To maintain the suppression of the pathological rhythm as long a possible, in the time segment T~3, an excitation is periodically applied at a frequency different from the resonant frequency. As soon as the amplitude of the desynchronized rhythm again exceeds a threshold value, the desynchronizatioa step i~c carried out anew so that the stimulation in the time segments T~ and T~5 is identical with the stimulation is the time segments T~~ and T~s.
Ia FIG. 4a the abscissa ie~ the time axis is arbitrary units and the ordinate gives the int.easity of the stimulation also is arbitrary units. FIG. 4a shows fcchematically the stimulation used for the frequency scan. In this case a periodic excitation sequence is applied whose frequency varies slowly and is this exan4ple slowly increases.
Ia FIG. 4b, the abscissa is the same time axis with the same units as is FIG. 4a. The ordir..ate indicates schematically is a sliding time window the amplitude obtained with time of the rhythm to be desynchronized, also ii, arbitrarily chosen units.
Corresponding to the excitation fre~ueacy which is illustrated by the pulse sequence shown is FIG. 4a, a resonance frequency is produced, i.e. a resonance is generated in which the amplitude of the neuronal rhythm increases. FIG. 5 illustrates phase resetting curves is which ~o over ~b is illust=~ated. ~, is the phase of the neuronal activity determined directly following stimulation or at a constant time delay after stimulatic-a. ~b is the phase of the 23158 Traasl. of PCT/DE2003/002250 neuronal activity determined either directly at the point is time at which the stimulation commences ~~r at a constant time interval prior to the commencement of stimul~~tioa. The phases q~" sad ~b are gives is radians. Each partial Fig~ire a) - f) corresponds to a series of test excitations with the same stimulus, that is as excitation with constant intensity rind excitation duration, applied with different values of the starti~ig phase fib. The effect of the excitation oa the phase dynamics fon the neuronal rhythm to be desynchronized was evaluated by means of the phase resetting curves. Ia the partial Figures a) i:o c), the mean gradient of the curve was equal to 1, while in part~.al Figures d) to f), the mesa gradient of the phase resetting cur~~es were equal to zero. By a "mean gradient" the gradient obtainE:d over a period of ~b is meant.
The transition between a phase resetting curve with a mesa gradient 1 to a phase resetting curve with a mesa gradient equal to zero is found between partial FIGS. c sad d in the region of the vertical arrow with respect to the previously' elevated phase fib. This value of the phase ~b is the vulnerable ph,sse of the neuronal rhythm to be desynchronized. The optimum value for the intensity lies between the two intensity values of partial Figures c) and d). To obtain this value one can either select va=iatioas approximating the intensities of c) and d) or precisely generating still further phase resetting curves with intensity values between those of c) sad d).
FIG. 6: flow diagram of the method of the invention.
_ g _ 23158 Transl. of PCT/DE2003/002250 FIG. 6 shows a flow diagr.~n of the method of the invention.
Initially there is a dete:rmiaation of the frequency spectrum under spontaneous conditio~is (1), that is without stimulation. whereby the patient is destressed and for example has his or her eyes open for 5 minutes find the eyes closed over a further period of 5 minutes. With c>pea or closed eyes, respective brain rhythms which are especially :ctroag or especially weak are obtained. For examwple the a rhythm is typically more strongly expressed with closed eyes and more weakly expressed by contrast with open eyes. A strong expressio=i of a neuronal rhythm mesas that this rhythm especially has a lt~rge amplitude. In this meaner the point width of the expression of the physiological or pathological rhythms which arise without stimulation can be determined.
Next a frequency scan is carried out (evaluation of the strength of the resonance by means c~f an amplitude determination of the excited rhythm), possibly togetb,er with determination of the quality of the eatraiameat over determination of the strength of the phase synchronization between the excitation sequence and the excited rhythm.
Depending upon the results from (1) sad (2), either of two different processes develop. Ia case the patient's natural sad aonpathological rhythmic activity is too weakly expressed or is mainly not present, a need-controlled synchronization is carried out is steps (3-5). Ia case the patent has a pathological rhythmic _ g _ 23158 Transl. of PCT/DE2003/002250 activity, a need-controlled desynch::onizatioa is carried out is steps (6-9).
The need-controlled synchronization (3) can be carried out in turn is two ways: is the coni:ext of a simple control function, at the beginning of a sen~;ory stimulation the excitation frequency f" and the intensity are established and maintained constant during the stimulation (4), Ia a preferred embodiment of the invention the stimulation is corunenced by values suitable for step (2) of the excitation frequenc3~ f" and the intensity (5). The control unit 4'matches however is this mode the parameters (especially the intensity) as coatrc~lled by need.
For the need-controlled dEayachronizatioa, initially the quality of the eatrainmeat evaluated (6) aa8 then a determination is made of the vulnerable phase (7), which - as described below -is associated with a determination c~f the optimum excitation intensity or excitation duration. 9~e need-controlled desynchronizatioa can then be effected is two ways: either a repetitive application of the seaso=y stimuli (8) is carried out or a restraining application is carried out (9). During repetitive application (8), the same desyachro=sizing excitation sequence is repetitively supplied whereas is thE: pauses therebetweea ao excitation is effected. During the continuous application (9) by contrast, sensory stimuli are coati=.uously applied and upon exceeding the threshold of the aeurc~nal activity to be desynchronized, the same desynchronizing excitation sequence is always applied.

23158 Transl. of PCT/DE2003/002250 Ia practically all of the steps, through the mesas for visualization (FIGS. 1 sad 6) a feeclback to the investigator can and should be provided.
Below the components of the device according to the invention are ~de~cribed in detail aid their functions explained.
The stimulator 1 is an exc;itatioa pulse generator which produces signals which can be coasc~.ously or unconsciously perceptible to the patient. Basica7.ly is this manner all signals which can be sensorially processed ~>y patients can be generated.
For example, visual excitation signt:ls, acoustic excitation signals or signals which excite the sense oi: taste or, less probably, signals which evoke the pain sense <:aa be mentioned. Visual excitations can include images or pt:tteras. The visual excitations can be outputted, for example, thromgh a special display screen 1a or spectacles or glasses provided with shutters ib. The display screen can for example be a project~.oa screen which through a shutter diaphragm with a projector vrhich displays a continuous image over time, provides the sensory response. The light-blocking mechanism for the shutter glasses om spectacles sad the shutter for the projector screen can operate prE:ferably either in accordance with the LCD technique or FLC (ferrc:electric liquid crystal) technique. The images and patterns which are used to evoke the visual responses can be those knows to the artisan. They can be, for example, Kanisza figures.
All tones or complex noises or sounds can be used as acoustic stimuli, like for example iterations of time-delayed broad band noise or sounds is the audible frequency range which can be 23158 Traasl. of PCT/DE2003/002250 outputted by a loudspeaker lc or het:d phones 1d. Aa excitation stimulator which can excite the sounds of taste or pain sensitivity can for example be a somatosensoric stimulation generator 1e or a time-modulated laser 1f. An excitat:ioa generator in the sense of the invention is thus a device for ~:roduciag a visual, acoustic or another sensory signal or stimulus. The stimulator 1 can output the signals described in a time-based pattern either rhythmically or arrythmically. This means that ~~isual images or patterns can be produced in a periodic sequence in time-spaced intervals of preferably 1 to 100 Hz or 1 to 70 H.; and/or is complex noaperiodic time-based .sequences although the az~plicatioa is not limited to these frequencies. Furthermore the intensities or amplitudes of the signals can also be varied. with visual excitations, not only csa the brightness be varied but thE: contrast can be varied as well. Analogously tones can be app7.ied in a periodic time-based sequence of preferably 1 to 100 Hz a,ad/or in complex nonperiodic time-based sequences. In addition, the sound amplitude can be varied. Analogously the same applies for the mesas for generating the other sensory stimuli in which =~ressure sad frequency can be varied. The complex nonperiodic time-based sequence of individual sensory excitations can, as described beloav, derive for example from a combination of a periodic excitation sequence with subsequent qualitatively individual excitations.
Ia health there is typically rhythmic activity is certain frequency bands and which arises is certain brain areas, for example one can observe so-called a rhythm (ca. 10 Hz) preferentially in the region of the visual cortex. In patients, 23158 Transl. of PCT/DE2003/002250 these physiological rhythms oa the sae haa8 may be less expressed or pronounced or oa the other hand ;nay have pathological rhythms present is them and which are chara~aerized by noatypical, meaning nonphysiological frequency bawds. ;~ pathological rhythm caw also be characterized by a normal freque~scy content but nontypical anatomical localization. A patholo~~ical rhythm need not only be limited to a single brain region but: can also affect other anatomically connected brain region~r by feeding the pathologica~.ly rhythmic activity thereto wad affeci:iag their functions.
The frequency contest of i:he brain activity of the patient has been characterized by the investigator, physiological rhythms which are insufficiently di~~tiact can be excited or excessively pronounced pathological rhythms can be suppressed or weakened. If pathological rhythms tire weakly expressed or pronounced, predominantly periodic f;timuli, which are outputted by the stimulator 1, caw excite these =~hythms. Ia a further step, through stimuli a desynchroaization of: the pathological rhythmic activity caw be effected. Then the signal sequences which are to effect the desynchronization can differ from those which enable the analysis or diagnosis is that these may toad to increase the pathological rhythmic activity. Foz desynchroaization at least owe desynchronizing pulse is produced.
The signals which are outputted by the stimulator 1 modulate rhythmic activity is certain brain areas is a manner which caw be detected by the sensor 2. The sensor 2 is is this sense a means for detecting brain activity. As exa~les of them, scalp-EEQ
electrodes are MEG sensors, that is SQ~7=D8, caw be mentioned. The 23158 Traasl. of PCT/DE2003/002250 apparatus is equipped according to ~~he invention with at least one sensor which is connected with the ~:oatrol unit 4.
The control wait 4 proces~3es the signal obtained from the season 2. The control unit 4 operai:es through means for carrying out the processed steps which have I~eea described is the application. This means can be esp~3cially a computer or as electronic circuit together with a ::omputer programmer a programmable processor like, for ext:nrple, a FPGA (field programmable array) which is capablea of carrying out the steps according to the invention of signa:. collection and evaluation and can control the stimulator 1 is the manner required by the invention.
It is especially advaatagE:ous to be able to practice the method with suitable processors. Tt~e term "processor" should not however be understood to be limited in any sense. It can be for example any optional unit suitable f'or carrying out computations.
It is possible for the processor to comprise a multiplicity of individual processors which are adv~.atageously assembled into an appropriate processor unit.
In the sense of the prese=.t invention, is addition; nay circuitry suitable for computation can be used. Advantageously, the circuit can be built into a com=~uter or incorporated is a logic component. The means of the descri=~tioa for carrying out the method steps of the invention are ccmpoaeats of the control unit 4 encompassing at least one component from the group comprised of a computer, as electronic circuit, a computer program or a processor.

23158 Traasl. of PCT/DE2003/002250 The means for controlling the diffe::eat method steps need not however be provided in a single dev:~ce.
The control unit 4 determ:lnes the degree of expression or development of a pathological rhythmic activity. If the pathological activity is not present: or is present only minimally, the control unit 4 provides control signals to the stimulator which can then output either no stimuli om other stimuli which differ either in frequency or amplitude or in frequency and amplitude from prior stimuli. Ia a diagnostic app:.ication the frequency and/or amplitude of the stimuli are varied until the pathological reaction is a maximum, that means that the rhythmic reaction of the pathological brain area is the strongest. This has the advantage that otherwise possibly nonnoticeab7.e pathological rhythms can be recognized under certain conditions is case at the point in time of the diagnostic investigation they m~.ght otherwise be too weak. Ia this case the control unit operates through means capable of calling up a maximum physiological t~ad/or pathological brain activity. This means operating for example through as electronic circuit, a processor or a computer toad associated software, ensures that stimulation sequences are prov5.ded as described below. The pathological rhythmic activity pattElra is analyzed by the control unit 4. The control unit 4 is adapted to provide another time-based pattern of the stimulus which is targeted to modulate the pathological activity and especially to suppress the pathological activity pattern or to attenuate it. Thus, opposite to the first effect, namely the promotion of the pathological activity, damping and, especially preferably, a compleae suppression of the 23158 Transl. of PCT/DE2003/002250 pathological brain activity is effecaed. The sensor 2 continues to detect the brain activity and with i:he control unit 4 analyzes the new state of the brain. Through a number of cycles of this type the control unit 4 is able to deterriine the stimuli with which the pathological conditions can be supp~~essed as completely as possible.
The receiver 5, which ser~~es for patient control is connected with the control unit 4. The receiver 5, in the sense of the invention can be for example a E~ush button or a switch or lever which is actuated by the patient. ~'he patient is instructed to actuate the receiver 5 in response t.o certain signals. Ia this manner the ability of the patient tc~ perceive the sensory stimuli or the treatment effect and the reac~tioa to the procedure can be controlled. The signals from receiver 5 are computed or processed in the control unit 4 sad are trans~iitted to the mesas 6 for monitoring the stimulation. Through. these mesas 6 the investigator can determine the guality of the stimulation and the result of its application to the patient. The de~~ice according to the invention eguipped with the receiver 5 and the means 6 for monitoring stimulation constitutes thus a preferred embodiment of the invention.
=n the application of the apparatus, two cases A sad 8 can be distinguished and are explaia,ed below by way of example.
A: For patients who naturall~~ have nonpathological rhythmic activity which is expressed too weakly or primarily or is usually not present.
- it -23158 Transl. of PCT/DE2003/002250 B: The patient presents with a pathological rhythmic activity is at least one region of ~:.he brain.
to cases A and B, the coa~:rol unit 4 operates is the following manner:
Frequency Scaa:
The frequency scan both iii case A and is case B is carried out initially. =n the freq»ency scan, a periodic sensory stimulation with an excitation freq~iency f" is carried out in which f~ varies slowly between preferably i and 100 Hz, especially ZO preferably between 1 to 60 Hz. Ia ~~IG. 4a this has been reproduced by way of example with sa increasing frequency of the applied signal sequence. Sensor 2 measures the neuronal activity and supplies it to the control unit 4 which determines in which frequency range the neuronal activity develops an excitation. This excitation can the be quantified by (i) integrating the amplitude of tt~e power spectrum over the excited frequency range or, aas.logously thereto (ii) determining the instantaneous E~litude of the frequency range by means of the Hilbert traasfc~rmatioa.
The device of the inveatic~a thus comprises means for carrying out a frequency scan as well as means for carrying out the step (i) and/or (ii).

23158 Transl. of PCT/DE2003/002250 The electronic circuitry msed for example for this purpose or equivalent means in control unit 4, as well as a computer program, which for example operates is accordance with the methods (i) and (ii) can serve as tl~e means for quantifying the neuronal activity.
This frequency scan can beg carried out by the control 4 which activates the means for geaer~~tiag sensor stimuli 1 so that the respective frequency is reproduced in the patient is the form of a sensory stimulus. For this pu~~pose the control unit 4 can act through mesas for controlling the stimulator 2, for example a TTL
pulse generator. The control unit ~~ recognizes the signals captured by the sensor 2 or their amplitudes is the investigative frequency range at which the excitataoa frequency produces a maximum excitation. The device thuf~ comprises advantageously such means which is capable of investigat:iag in the signals measured by the sensor 2 apart form the frequeac~y range of the excitation frequency also other frequency rangE:s. This means can carry out time-dependent frequency analysis b~.sed upon Fourier transformation or wavelet analysis. For this purpose the control wait 4 comprises a means which is suitable for carrying out these steps. Such mesas can be as has been described above try say of example, a computer, an electronic circuit, a processor, a programmable electronic circuit (FPGA) or a computer program. The frequency of the excited activity can thus coincide with the excitation frequency or can also not coincide therewith. Surpr3.singly it has been found that the frequency of the periodic stimu7.us sequence which serves for entraiameat follows the law gives below:

23158 Traasl. of PCT/DE2003/002250 f /R / f" = n / m Formula 1 where f" = the excitation frequency,. that is the frequency of the periodic stimulus sequence serving for excitation fR = the frequency of the exc:.ted neuronal activity (resonance frequency) whereby a and m are small whole nuni~ers, that means < 10, (namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) for ~axample, a/m = 1/1, 1/2, 2/3 etc.
With the aid of the frequ~3ncy scan, two aspects of the excitation properties are explored.
1. A determination is made as to whether as excitation will bring about a physiological rh~~thm is a frequency range expected for this rhythm. With flicker light stimulation, these frequency ranges can be for example is the region of 10 Hz, 20 Hz, 40 Hz and 80 Hz. In this case a det.ermiaatioa is made whether a physiological rhythm, which may be c~f pathological origin or can develop spontaneously, that is without stimulation, is too weakly expressed. can be excited by periodic stimulation.

2. A determination is mace as to whether as excitation will lead to a pathological rhythm. The latter is characterized by a physiological response that does n.ot lie is a physiological frequency range or is is a physiological frequency range but arises at as untypical brain region. The Physiological frequency ranges are the frequency ranges at which neuronal rhythms naturally occur.

23158 Transl. of PCT/DE2003/002250 For example. the a rhythm in the re~aioa of about 10 Hz gad a rhythm in the region of about 20 Hz can be mentioned. Ia this manger a determination is made as to whether a pathologically generated rhythm can be produced by a periodi~: stimulation. Such pathological rhythm is typically, although not necessarily already present under spontaneous conditioa,a, that is without stimulation.
After the frequency scan :Ls carried out as described above, the application of the iaven~:ioa is effected in accordance with cases A and H below.
A. Need-Controlled Synchronization:
The goal of the need-controlled synchronization is, with patients who have one or more too weakly expressed physiological rhythms to excite that by sensor st:.muli during treatment. For this purpose the stimulus treatment which is found to be required because of the weakened physiologic~~l rhythm is improved or enabled. For this purpose the sensmr 2 registers the neuronal activity of the brain area to be excited. The signals measured by the sensor 2 are advantageously supplied to the control unit 4 through as isolating aa~lifier 3. 9!he control unit 4 can then control the sector stimulation is twc~ different wayss 1.) Ia the framework of ~, simple control function, at the beginning of the sensory stimula,tioa the sensory stimuli or pulses are applied with as excitatic~a frequency f" gad the intensity according to the results c~f the frequency scan. These 23158 Traasl. of PCT/DE2003/002250 stimulation parameters remain const~int during the sensory excitation.
2.) As under (1), the ex~:itatioa is commenced with as excitation frequency f" and the inte:asities which are appropriate from the results of the frequency s~:aa. The control unit 4 matches these parameters during the sensory excitation under need control.
That means that the control unit 4 reacts to a decrease in the amplitude of the rhythm to be excite3d with an increase in the intensity of the exciting stimulus. Ia this case the control unit 4 acts through means for registerias~ the change is the amplitude of the rhythm which is to be excited tc~ change the excitation intensity. For this purpose as has been described by Way of example above, a computer, as elect~-oaic circuit, a processor, a programmable electronic circuit (FP(~) or a computer program can be used. The range of intensities use<L is this case is limited at its upper level by safety consideration, this mesas as avoidance of the triggering of an epileptic response.
During the sensory stimult~tioa described under (1) or (2), the patient is subjected to dei:ined stimuli like, for example Kaaisza figures. The patient is prE:viously instructed to look for special features is these stimuli. By feedback over the push button 5, the patient can control whether the-recogaition of the sensory stimulus to which the patie=nt is subjected is improved or enabled by the excitation of the physiological rhythm. By at least one and preferably three hiatuses im the reaction of the patient, a suitable signal frown the control uai.t 4 is provided to the means 6 for monitoring the stimulation sad thus supplied to the 23158 Transl. of PCT/DE2003/002250 investigator. This signal serves to let the investigator know whoa the patient is not willing or is not in a position to process the sensory stimulation is accordance with the predetermined requirements as set out above.
B. Need-Controlled D~ssynchronfzatioa:
The goal of the need-controlled desyachroaizatioa is to damp or suppress one or more pathological rhythms which may be too strongly active or expressed during the processing of sensory stimuli. For this purpose, the stimslus processing which may be destroyed by an excessively expresse~3 neuronal rhythm should be improved or enabled. This result is achieved with the device according to the invention and especially with the control unit 4 or the above-described mesas forming part thereof and functioning as described is the following.
The sensor 2 registers, fo,r this purpose, the neuronal activity of the brain area to be dam~aed. The signals measured by the sensor 2 are supplied to the con~;.rol unit 4, preferably through the isolating amplifier. The control unit 4 operates, according to the invention, is accordance with th~3 following principle:
A rhythmically active neur~~aal population can be desynchronized with a sensory stimuhis whey the stimulus or excitation oa the one hand has the c~~rrect intensity gad duration gad, oa the other hand, is applied im a critical phase of the corrective oscillation of the neuron~il population, the so-called vulnerable phase. Because of the uaaivoidable variability of the frequency of a neuronal population, ;Lt is difficult to determine 23158 Transl. of PCT/DE2003/002250 precisely the vulnerable phase. This problem is solved is accordance with the invention by this use of complex stimuli. These are comprised of two gualitatively ~iiffereat stimuli or excitations or pulses:
The first stimulus coatro:Ls the dynamics of the neuronal population such that at the end of i:his stimulus the dynamic state of the neuron population is knows w:.th sufficient precision. For this purpose as entrainment is carr:.ed out, that is; as entraining periodic stimulus for excitation sequence is applied 3a order to bring the dynamics of the neuron po~~ulatioa into step with the stimulus sequence. To this end, thE~ device according to the invention, through mesas for effecti.ag an eatraiameat, that is a periodic stimulation for the purposE~ of controlling the rhythm, meaning the phase dynamic, can cont~~ol the excitation of the neuronal activity. This can be ach~.eved as has bees indicated is greater detail by example above, with a computer, an electronic circuit, a processor, a programmable: electronic circuit (FPGA) or a computer program.
The second stimulus or excitation follows the first, entraining stimulation (the stimulation sequence) with a substantially constant time lag. It encounters the pathologically synchronized. neuronal population it. a vulnerable state sad gives rise, is this way, to a desyachronfzatioa. The second stimulus or excitation pulse is comprised advantageously of only a single stimulus or excitation pulse, or a short periodic stimulus or pulse sequence, which can be comprised of at least two individual stimuli or pulses and advantageously not more thaw tea individual stimuli 23158 Traasl. of PCT/DE2003/002250 or excitation pulses. To this end, the device of the invention is provided with means for desynchroni::atioa. Such means, as has also been indicated by example above, cam be a computer, as electronic circuit, a processor, a programmable: electronic circuit (FPGA) or a computer program which is capable oi: carrying out the process steps described below.
The stimulation parameters; required for the desyachroaizatioa are determined is accordance with the invention by the following standardization procedure.
1.) Monitoring the quality of the entrainmeat:
a stimulus for excitation pulse seqL.eace comprised of k preferably identical stimuli or excitation pul es are applied one time, preferably tea to one hundred times. =a this case, a small values are varied as above until the entrainmeat is good enough. The quality of the entrainment is then investigated is the following manner or quaatifieds the phase and the amplitude of the neuronal rhythm to be desynchronized are detersniaed preferably by the Hilbert transformation. An alternative method can be the matching is a sliding time window of the signal of the neuronal rhythm with a slowly varied sine function. For this purpose, the device according to the invention is provided with means for testing the quality of the entrainmeat. Such means can be, as has bees indicated is as exemplary way above, a computer, as electronic circuit, a processor, a programmable electronic circuit (FPGA) or a computer program which carries nut the described steps.

23158 Traasl. of PCT/DE2003/002250 The effect of the entrain~nent is that after the entraining stimulation, the neuroaa:l rhythm will always have the same amplitude and above all always the same phase, independent of the amplitude and the phase at the l~eginaing of the stimulation.
To ensure that this will be the cas~a, the phase or preferably the phase and amplitude are evaluated b~~ means for evaluating phase and amplitude or is a less preferred embodiment of the invention, exclusively by means for evaluating the phase of the neuronal rhythm in the following manger. Fon this purpose as has bees described above by way of example, t:he described steps can be carried out by a computer, sa electnoaic circuit, a processor, a programmable electronic circuit (FPC~A) or a computer program.
For the first applied sti~~ulus or excitation pulse sequence, which is comprised of a iz~dividual stimuli or excitation pulses, the mesas for carrying out ~. phase resetting can produce a so called phase-resetting curve. A phase resetting curve is a phase response curve in which the pr.ase at the end of the stimulation for all m applied excitt.tioa or stimuli sequences. A
perfect eatrainmeat is obtained whe=. a horizontal phase resetting curves, that is a phase resetting curve which is independent of the phase at the beginning of the stimulation always assumes the same value as the phase at the end of the stimulation.
The phase resetting curve can be displayed to the researcher for example by a display screen forming a means for visualization 6. C~ the other head, the phase resetting curve can be used to evaluate the value of the phase at the end of the stimulation, for example by a simple mathematical operation like 23158 Traasl. of PCT/DE2003/002250 determination of the standard deviai:ioa of the value of the phase, or the quality of the match of a horizontal line to the phase resetting curve by mesas for the qu:~atitative characterization of the phase resetting curve. Such met~as, as has also been indicated in as exemplary manner above, can bE~ a computer, as electronic circuit, a processor, a programmablE! electronic circuit (FPGA) or a computer program which is designed t.o carry out the described steps.
Preferably the quality of the entraiameat is determined exclusively visually by the investi~~ator through the means for monitoring the stimulation 6. The amplitude ie determined is the same way by means of amplitude resetting curves. The device of the invention can then include mesas fo= determining the amplitude sad for carrying out an amplitude resetting which operates is the following meaner. For this purpose the apparatus can include. as was described above is as exemplary manner, a computer, as electronic circuit, a processor, a programmable electronic circuit (FPGA) or a computer program which can carry out the aforedescribed steps. Ia the amplitude-resetting curves, that is amplitude response curves, the amplitude at the end of the stimulation is plotted against the amplitude at the beginning of the stimulation for all m applied stimulation or excitation sequences. A perfect eatraiameat leads to a horizontal amplitude resetting curve, that mesas, independent from the amplitude, at the beginning of the stimulation the amplitude at the end of the stimulation will assume always the same value. The amplitude resetting curve is evaluated - as -23158 Traasl. of PCT/DE2003/002250 like the phase resetting curves quantitatively and/or and preferably only visually.
The number of stimuli or excitation pulses following one another in a pulse sequence k is ia~~reased until the eatrainment is sufficiently good is terms of ampli~:ude and phase.
Ia as alternative and pre:Eerred embodiment of the invention the quality of the eatrai~uneat is examined is the following manner and quantified. Tlie goal of this alternative procedure is to monitor the quality of the entraiameat not only at the end but during the application c~f the entire stimulus or excitation sequence. This makes thc: determination of the quality less dependent oa fluctuation of the: measured neuronal dynamic which can be affected either by the measurement process or above all by intrinsic neuronal noise. Fc~r this purpose, a stimulus sequence comprised of k preferably identical stimuli or excitation pulses is applied one time and prefE~rably tea to one hundred times.
R is then varied by small values as described above until the entraiameat is good enough. The quality of the entrainment is investigated or quantified is the fc~llowiag manner:
The signal representing t~.e excited neuronal activity measured by the sensor two is filtered is a band pass filter which conSpletely contains the frequency peak f,~ (formula 1) of the resonance frequency but does not contain other frequency peaks, the harmonics, subharmoaic or other physiological or pathological rhythms. Using the Hilbert transformation, the phase ~R, that is the phase which is determined from the band pass filtered signal is this meaner. Apart from this, the phase ~" is determined, that is 23158 Transl. of pCT/DE2003/002250 the phase of the excitation stimulue~ sequence or excitation sequence. This can be achieved is t:wo ways: either a sine function can be matched to the stimmlus sequence such that the maximum of the signed function will coincide with the point is time at which the individual stimulus is applied. The phase ~" is then the phase of the matched sine fuacti.on. Alternatively, the signal which represents the stimulus seque=,ce and thus the sequence of rectangular pulses which correspond to the excitation frequency f"
of formula 1 and the band pass filter is selected. The phase ~" is then the phase determined by the Hilbert transformation of the band pass filter signal of the stimulus sequence. The band pass used for this purpose must be so selectec. that it completely encompasses the frequency peak ,f'" is the spectrum of the signal of the excitation sequence but contains no other frequency peak. Then the n:m phase difference a~" - mob betweE:a the excitation stimulus seguence and the excited neuronal activity is determined. The strength of the eatrainment is then preferably determined by means of the azm - eatrainment index which is defined as follows: is the time window used for determining the quality of the eatrainmeat, the distribution of the a:m phase difference is detenaiaed. The entropy S of this distribution is then determined according to the formula 2 N
S = - ~ pk In pk ( Formula 2 ) k=1 - a8 -23158 Traasl, of PCT/DE2003/002250 whereby, pk is the relative probability that the value of the n:m phase difference will be found is tl~e k th case bin. The number of the bias N is typically determined :.n accordance with formula 3:
N = exp(0.626+0.41.a(M-1)1 (Formula 3) whereby M is the number of measured values of the n:m phase difference during a stimulus sequence.
The a:m entraiameat index ea,' is calculated is accordance with formula 4 en~ = S S S (Formula 4) whereby S~ is the entropy of as equ,tlibrium, that is S",~ ~ In N, whereby the optimum cumber for determining the distribution is terms of equidistance partial iatervsls or bias is given by the formula 3. Through the mesas of for.~ula 4 a normalization is carried out such that O s en,= s 1. a:a,= = 0 means that ao entrainmeat is present while ea,~ ~ 1 corresponds to a perfect entrainmeat. The larger the value of ea,~, the better is the eatraiament.
values of ea,s are obtained for each applied stimulus sequence. From that value the mesa value 23158 Traasl. of PCT/DE2003/002250 t En,m - l ~ enJm ( Formula 5 ) ~=i is calculated whereby en~m is the j-':h stimulus sequence. The relationship 0 s Ea,= s 1 applies. The number of the k stimuli or excitation pulses in a stimulus seqv ence following one another is increased until the entrainmeat is ~ufficieatly good, that is until Ea~m sufficiently approaches one.
2.) Determining the vulnerable phase:
The vulnerable phase depends upon the intensity and the duration of the sensory stimulation. Advantageously the duration of the sensory stimulus is held constant is the frame v~ork of the standardization procedure while the intensity and the vulnerable phase are so varied, as described below, that the desynchronizing effect of the stimulation is maximized.
The determination of the vulnerable phase is carried out with means for determining the vulnerable phase. Such means, as has been indicated above by v~ay of example previously, can be a computer, sa electronic Circuit, a processor, a programmable electronic circuit (FPGA) or a computer program which can carry out the steps described is the following. Ia this case the device according to the invention can operate in two different ways:
A) the time spacing betwee:a the last stimulus or excitation pulse of the entraining stimulus or excitation pulse of sequence and the desynchronizing pulse on the one hand and the 23158 Transl. of PCT/DL2003/002250 intensity of the desynchronizing stimulus are varied by mesas for varying the time spacing between th~3 last stimulus of the entrainmeat and the desynchronizing stimulus between preferably 0 sad 2 period lengths of the mean frsquency of the frequency band associated with the pathological rh_rthm is a systematic manner, preferably in small equidistant stews. The mesas used for this purpose as has bees described by wa:r of example above, can be a computer, as electronic circuit, a ~>rocessor, a programmable electronic circuit (FPGA) or a comp»ter program. This variation in the time spacing is carried out sysi:ematically for different values of the intensity by mesas of a meaaE~ for varying the intensity.
Preferably the intensity is increasE~d is small equidistant steps and for each value of the intensity, the time spacing is determined as described above between 0 and 2 =~eriod lengths. The variation of the time spacing and the intensity is carried out preferably by the control unit 4. The optimum value for the intensity of the sensory stimulus and the time spacix.g between the last stimulus of the eatrairuaent sad the desynchronizing stimulus is the value at which the strongest desyachroaizatica effect arises, that is the amplitude at which the desynchronized rhythm after stimulation is the smallest. The amplitude is preferably determined by band pass filtration with subsequent Hilbert transformation.
Alternatively, the amplitude can be determined either by a matching of a slowly vazying sine function to the band pass filtered signal of sensor two is a time window after stimulation or by determining the integrated amplitude over the frequency bead of 23158 Transl. of PCT/DE2003/002250 the power spectrum of sensor two is a time window after stimulation.
B) The time spacing is varied under A). Differing from A), the intensity is not increased is equidistant steps but is varied systematically is the following way: is this case phase resetting curves are used with which the effect of the desynchronizing stimulus on the pha~ae dynamics of the neuronal activity~to be desynchronized is in~restigated. The phase ie advantageously determined by means «f bead pass filtration and a subsequent Hilbert transformation oi: the signals measured by the sensor two. Alternatively to the use of the Hilbert transformation, a slowly varying si=~e function is a sliding time window can be matched to the band puss filter signal of sensor two.
The limits of the pass ba:~d can then be the limits of the frequency bawd of the pathological x~euroaal rhythan which is detenained at the outset. When reference is made to the phase resetting curves, ~" over ~b are obt~.ined by a mesas for applying ~~, the phase of the neuronal activity after stimulation, over cpn, the phase of the neuronal activity at the beginning of the stimulation.
Such means can be a means for investigating the effect of the desynchronizing stimulus on the phase dynamics of the neuronal activity to be desynchronized. Such mesas can as has been indicated above by way of example, be a computer, an electronic circuit, a processor, a programmable electronic circuit (FpGA) or a computer program.
is thus the phase of thES neuronal activity which is determined either directly after stianulatioa or with a constant 23158 Traasl. of PCT/DE2003/002250 time delay following stimulation. 'this time delay should preferably be smaller than one period length of the neuronal rhythm to be desynchronized or better stil:. is equal to 0. Since the period length of the neuronal rhythxi is varied with time, when the reference is made above to period lE:agths, the period length averaged over time is meant.
ibis the phase of the aeuwonal activity which is detexinined either directly at the pc~iat is time that the stimulation coimneaces or at a consta.at time interval prior to the comtnencemeat of stimulation. The time interval should be, by analogy with the determination of ~~, as small as possible or better still equal to 0. The time interval is the determination of cp~ or ~b should be as small as possible to ensure that time dependent variation is the period length will not influence the quality of the evaluation.
If the selected intensity of the sensory stimulus for desyachroaizatioa is too small, the phase resetting curve will typically have a mesa rise of one. If, by contrast, the intensity is too large, the phase resetting curve will typically have a mean rise of 0.
The optimum intensity value and the optimum value for the lag between the last eatraiament pulse and the desynchronizing pulse is determined with precision b;~ the location in the phase resetting curve at which the transition from a mesa rise 1 to a mesa rise 0 occurs.
This has bees shows in FIG. 5. F=G. 5a through 5f respectfully show phase resetting curves, whereby in the individual 23158 Traasl. of PCT/DE2003/002250 partial figures, the intensity of t:ze sensory stimulus is constant but different from one of the parti~il figures to another and indeed increases from the smallest value im FIG. 5a to the largest value is FIG. 5f. The optimal stimulatio~i parameter is thus found at the transition from FIG. 5c through 5e ut the location marked by the arrow, (i) the mean value of the ini:easity belonging to FIGB. 5c and 5d is optimum for the selected :stimulus duration at which the desynchronizatioa intensity is the ~strongest and (ii) the inflection point indicated is FIG. :id with the arrow indicates the phase ~b which is optimal for the selected stimulus duration to which corresponds to the strongest itesyachroaiziag time interval between the last stimulus of the ent:rainment and the desynchronizing stimulus. This timE~ interval can either be given is absolute time values or, analogously thereto as illustrated in FIG. 5 in terms of the phase of the neuronal activity. With the phase resetting curves it is possible to provide a x-axis equivalent to ~b giving as absolute time interval between the last excitation of the entraiameat and tr,e desynchronizing excitation.
If the experimental data are strongly affected by noise, the phase resetting curve can be used to provide a pair of values comprised of intensity and ~b by multiple meas~iremeats and the mean value of ~, is then used.
The control unit 4 controls the sensory stimulation is two different ways. The need-controlled desyachronizatioa can either be carried out repetitively or continuously. Ia both functional methods, an entraiameat is used for the effective desyachroaization. The frequency of the entrainment, that is the 23158 Transl. of PCT/DE2003/002250 rate of the entraining sequence of sensory stimuli, is determined is a previous frequency scan. In that frequency scan it is determined which excitation frequency f" provides a maximum amplitude of the pathological rhythm. If the excitation frequency f" is identified or a plurality of e:~citatioa frequencies are identified, a desynchroaization can be commenced. Ia the case that a plurality of excitation frequencies are found which lead to maxima is the amplitude of the pathological rhythm, the desynchroazatioa is carried out for the one which has the strongest entrainmeat effect, that is the strongest excitation of the amplitude.
a) Repetitive Application:
Ia the repetitive application, the same desynchronizing stimulus or excitation sequence is r~apetitively applied: Ia the pauses between these desynchronizing stimulus or excitation sequences no stimulus or excitation :Ls applied.
The patient is instructed before commencement of the need-control desynchronization by as investigator or by the device itself. That mesas that the patient is either told by the investigator how he or she should reiapond to the repetitively applied stimulation or excitation sectueaces or the device itself can signal this to the patient by fo~~ example by visual or auditory instruction: the patient hears or rends what he or she is to do.
For example, the patient angst try, upon visual stimulation with the repetitively ap~~lied visual stimulus pattern, of certain objects or individual patt:eras, for example Kaaisza 23158 Traasl. of PCT/DE2003/002250 figures to compare them with one another or count them. The investigator controls, using the means 6 for monitoring the stimulation, preferably the effect <>f the stimulation of the brain activity and the information proces:ciag by the patient which is determined by feedback via the push button 5. The patient must for example, each time he recognizes a c:ertaia partial pattern, press the push button 5. In this manner t:he investigator is able to determine whether the applied senso=y stimulus improves or enables the damping or suppression of the pathological rhythm. If the reaction of the patient is missed at least one time, as appropriate signal is provided by the control u~.it 4 to the means 6 for monitoring the stimulation and thus is communicated to the investigator. This signal serves tc inform the investigator that the patient is not willing or is not capable of processing the sensory stimulus in accordance with the predetermined conditions.
The control unit 4 controls the application of the sensory stimuli is the following manners Aa entraining periodic sequence of sensory stimuli or excitation is applied with the optimum excitation frequency f".
The sensory stimuli or excitation here used can be identical although they need not necessarily be identical. Breferably the sensory stimuli used with respect to the following parameters are identical in order to ensure as effective entrainmeats (i) They are of the same quality, that is that they deal for example always with the same visual pattern.

23156 Traasl. of PCT/DE2003/002250 (ii) They have the same intensity, that is for example the same light or sound amplitude.
(iii) They have the same contrast, that is for example .in the case of visual stimuli, t:ae same light-dark contrast.
(iv) They have the same durati~~n.
With a constant lag. there is thereafter effected an application of the desynchronizing stimulus or exc:ltatioa is a vulnerable phase state of the pathological rhythm. '.'he desynchronizing sensory stimulus is preferably of the same modality, that is, when the entraining stimuli are visual stimu:.i. the desynchronizing stimulus is also a visual stimulus and for a»ample is without an auditory stimulus.
The desynchronizing stimu7.us need not hpwever be of the same quality as the entraining stimuli. Preferably however it is of the same quality. that is it usef~ for example the same visual patters. The desynchronizing stimuJ.us differs however preferably from the stimuli of the entraining E~timulus sequence by its duration and/or its intensity aad/o=' its contrast.
AS soon as the desynchronizing stimulus is applied, there is a transitory period is which no stimulus is present. Ia connection with this stimulus application, the patient advantageously must signal via the Push button whether he has bees able to detect for example special cbjects or visual patterns therein.
Following such a desynchronizing stimulus, there is a pause whose duration can lie within a statistical distribution is a 23158 Tran8l. of PCT/DE2003/002250 predetermined interval, preferably ~~ uniform distribution. During this pause no stimulus is applied. After this pause, there is a repetition of the collective of den=tnchronizing stimuli, comprised of another entraining stimulus sequ~3ace and as individual desynchronizing stimulus.
=a the framework of the r~:petitive application, the control unit 4 determines whether tl~e desynchronizing of the pathologically active neuronal popu~.atioa has been effected, that is whether the damping of the patho7.ogical rhythm has bees strong enough. Should this be the case thE: repetition of the stimuli is continued. If the damping of the pt~thological rhythm is insufficient at least once, restanda.rdizatioa must be carried out with the above-described standardizr.tioa procedure.
F=G. 2 shows an excitation. with the resonance frequency which is followed by a desynchronization pulse fa the vulnerable phase. In this Figure the x-axis represents the time and the y-axis the intensity of the sensory stimulus.
b) Continuous Application:
Hy contrast with the repetitive application (a) in the continuous application, there is a permanent sensory stimulus.
Whenever the neuronal activity exceeds a threshold of the above-determiaed amplitude of the neuronal activity to be desynchronized, a desynchroaizatioa is carried out. For this purpose as entraining pulse sequence is followed by the application of at least one single stimulus (FIG. 2). Ia the time between the ~

23158 Traasl. of PCT/DE2003/002250 desynchrizatioas, a continuous sens~~ry stimulation applies. In this case there are two possibiliti~3s:
I) Ia the time between tote desyachronizatioa, stimulation is carried out with a pEiriodic sequence of sensory stimuli or excitation pulses. This sequence is comprised of identical individual stimuli which tire applied at a frequency sufficiently different from the resc~naace frequency that no resonance arises.
II) In the time between tr,e desyachroaizatioa, stimulation is applied with a random sequence of sensory stimuli or excitation pulses. The individual stimuli of this sequence are comprised of identical visual or auditory patterns is which the following parameters are statistically varied from stimulus or pulse to stimulus or pulse: with visual stimuli the contrast and/or the brightness can be varied. With auditory stimuli the sound volume can be varied. Ia addition, the pauses between the individual stimuli and the duration of the individual stimuli can be statistically varied. Ia the statistic variation, the corresponding parameters can be varied 'between the normal physiologically experimental limit or uniformly.
The purpose of the stimulation described above under Z
and II is, 1. to continuously supply sensory stimuli to patients which can be processed by them so th~st the patients can continuously have available the required action, for example, the ' CA 02493305 2005-O1-27 23158 Traasl. of PGT/DE2003/002250 detection of visual partial images. and 2. to prevent thereby a resonance of the pathological rhyth:a from developing.
Figure 3a shows a sequence; of stimuli by way of example for the mesas 1 for generating the :;easory stimuli is the form of a time-spaced application of patterns as the sensory stimuli whereby variant I, that is a periodic stimu7.atioa between the desynchroaization, is used. Ia Figwre 3b the associated activity pattern of the pathologically effected brain region has bees gives.
In Figures 3a and 3b the x-axis is the time axis is each. Ia FIG.
3a the intensity of the stimulus is plotted along the y- axis. Ia Figure 3b the amplitude is a function of time is a sliding time window for the neuronal activity to be desynchronized has bee;a plotted.
Ia Figures 3a and 3b, the time regions T1 sad T'1, Ts sad T's, T3 sad T' 3, T, sad T',, as well ago Ts sad T's are identical . Ia the time regions Tl or T' 1, the an~pl~.tude of the pathological rhythms because of resonance is a maximum. Ia the time regions Tz or T',, a desynchronizing sensory stimulus is applied fa the vulnerable phase to either completely suppress the pathological activity or at least reduce its intensity. This gives rise to a drop is the amplitude is Figure 3b.
As has bees described under I above in the time region T, a periodic stimulus sequence is applied whose frequency differs sufficiently from the resonance frequency is the time region T1.
The effect in the time region T'3 is that is spite of the sensory stimulation the pathological rhythms will recover only slowly.

' ' CA 02493305 2005-O1-27 23158 Traasl. of PCT/DE2003/002250 Ia the second case II, is the time region T3, instead of a periodic stimulus sequence a raad~~m or stochastic stimulus sequence is used. With this featur~3 the pathological rhythm is suppressed as long as possible.
Ia Figure 3b this phase i~a characterized by the segment T~3 is which the curve of the brain activity to be suppressed reaches its minimum value. As soon as the brain activity is the time region T~3 again exceeds a threshold value, the need state for desynchraaizatioa arises so that is the ae~xt time region T~ a new desynchronization operation is carr3.e8 out. For this purpose in the time region T4 the same entrainment is effected as is th~ time region T1. Following the entrainmeat, in the time region Ts, a desynchronizing stimulus is applied as is the time region Ts. For this purpose the sensor 2 registers the increased activity of the pathologically affected brain regiox. an8 reproduces the signal at the control unit 4 which triggers tb.e next desyachronization. In conjunction with the desynchronization effected is the time region Ts, a periodic stimulus sequence is ~~ppli.ed anew as is the time region T3, with a frequency sufficiently different from the resonance frequency. It corresponds to the above-described case I.
Alternatively thereto, also according to the above-described case II, stochastic or random stimulus sequences can be used.
The invention comprises a computer program with program code mesas for controlling a device rahich can carry out at least one of the preceding method steps or optional combinations of at least two of the method steps gives is this description when the program is run oa a computer. The invention also encompasses a 23158 Tranel. of PCT/DE2003/002250 computer program product with progrt~n code meaas which is stored oa a computer-readable data carrier anti permits the method to be carried out as defiaed by that compmter program. This computer-program product caa for example be :~ diskette. The iaventioa also comprises as electroaic circuit whi<:h is suitable for carryiag out the iastructioas of the computer program or the computer program product.

Claims (37)

1. A device for need-controlled modulation of physiological and/or pathological neuronal rhythmic activity, comprising a control unit (4), a stimulator (1) and at least one means for detecting brain activity (2) which is connected with the control unit (4).

2. The device according to claim 1, characterized in that the stimulator (1) is at least one component from the group comprising a display screen, a pair of shutter-equipped eyeglasses, a loud speaker, headphones, a pressure generator and a time-modulated laser.

3. The device according to claim 1 or 2, characterized is that the means for detecting brain activity is at least one component from the group comprised of a scalp EEG electrode or a MEG electrode.

4. The device according to one of claims 1 to 3, characterized is that the means for detecting brain activity is connected with the control unit (4) by as isolating amplifier (3).

5. The device according to one of claims 1 to 4, characterized is that it comprises a means for feedback of a patient reaction (5) which is connected to the control unit (4).

6. The device according to one of claims 1 to 4, characterized is that it comprises means for evoking a maximum physiological and/or pathological brain activity.

7. The device according to claim 6. characterized is that it comprises means for carrying out a frequency scan.

8. The device according to one of claims 1 to 7, characterized in that it comprises means for quantifying the neuronal activity.

9. The device according to claim 8, characterized is that the means for quantifying the neuronal activity is a means for quantifying the amplitude of the power spectrum over the excitation frequency range or a means for quantifying the instantaneous amplitude of the frequency range as determined by the Hilbert transformation.

10. The device according to one of claims 1 to 9, characterized in that the control unit (4) is joined with a means for actuating the stimulator (1).

11. The device according to one of claims 1 to 10, characterized is that it includes means for investigating the signals measured by the sensor (2).

12. The device according to claim 11 wherein the means for investigating the signals measured by the sensor (2) carries out a Fourier transformation or a wavelet analysis.

13. The device according to claims 11 or 12, characterized in that it comprises means for registering the change in the amplitude of the rhythm to be excited.

14. The device according to one of claims 1 to 13, characterized in that it comprises means for carrying out as entrainment.

15. The device according to one of claims 1 to 14, characterized in that it comprises means for desynchronization.

16. The device according to one of claims 1 to 15, characterized is that it comprises means for testing the quality of the entrainment.

17. The device according to claim 16, characterized is that the means for testing the quality of the entrainment comprises a means for determining the phase or the phase sad the amplitude of the neuronal rhythm to be desynchronized.

18. The device according to claim 17, characterized is that the means for determining the phase and amplitude of the neuronal rhythm to be desynchronized carries out a Hilbert transformation or a matching of the signals of the neuronal rhythm with a slowly changing sine function is a sliding time window.

19. The device according to one of claims 1 to 18, characterized is that it comprises means for evaluating the phase and amplitude of the neuronal activity.

20. The device according to claim 19, characterized is that the means for evaluating the phase and amplitude of the neuronal rhythm contains a means for calculating phase resetting curves.

21. The device according to claim 20, characterized is that it comprises means for visualization (6) of the phase resetting curves.

22. The device according to claims 20 or 21, characterized is that it comprises means for the quantitative characterization of the phase resetting curves.

23. The device according to claim 19, characterized is that the means for determining the amplitude is a means by which the amplitude resetting curves are effected.

24. The device according to one of claims 1 to 23, characterized is that it comprises means for determining the vulnerable phase of the neuronal rhythm.

25. The device according to claim 24, characterized is that the means for determining the vulnerable phase is a means for varying the time spacing between the last excitation of the entrainment and the desynchronizing excitation signal.

26. The device according to claim 25, characterized in that the means for varying the time spacing between the last excitation of the entrainment and the desynchronizing is a means which effects a variation is the time spacing for different values of the intensity.

27. The device according to claims 25 or 26, characterized in that the means for varying the intensity is a means for increasing the intensity is equidistant steps.

28. The device according to one of claims 24 to 27, characterized in that it includes a means which enables from a series of test stimulations optimal stimulation parameters to be determined.

29. The device according to claim 28, characterized in that it includes means which detects stimulation parameters from a series of test stimulations from which a minimization of the amplitude of the neuronal activity to be desynchronized can be obtained.

30. The device according to claim 29, characterized is that the means for determining the minimization of the amplitude of the stimulation parameters which give rise to a desynchronization of the rhythm comprises a means for carrying out the Hilbert transformation.

31. The device according to claim 29 or 30, characterized is that the means for determining the minimization of the amplitude of the stimulation parameters giving rise to a desynchronization of the rhythm combrises a means for matching a slowly changing sine function to a signal of the sensor (2) in a time window following stimulation.

32. The device according to one of claims 29 to 31, characterized in that the means for determining the stimulation parameters giving rise to a minimization of the amplitude of the desynchronizing rhythm comprises a means for integrating the amplitude of the power spectrum over the frequency band of signals measured by the sensor (2) is a time window following the stimulation.

33. The device according to one of claims 20 to 32, characterized is that it comprises means for increasing the intensity in non-equidistant steps.

34. The device according to one of claims 20 to 33, characterized is that it comprises a means for evaluating phase resetting curves with which the effect of the desynchronizing excitation pulse on the phase dynamics of the desynchronizing neuronal activity is investigated.

35. The device according to claim 34, characterized in that the means for evaluating the phase resetting curves comprises a means for applying .PHI.~, the phase cf the neuronal activity before stimulation, over .PHI.b, the phase of the neuronal activity after stimulation.

36. The device according to claims 34 or 35, characterized in that the means for evaluating the phase resetting curves comprises a means for determining the position of the phase resetting curve at which the transition from a main rise 1 to a main rise 0.

37. The device according to one of claims 1 to 36.
characterized is that it includes a means for monitoring the stimulation (6).